Biodegradable radioactive particles

ABSTRACT

Particles, preferably substantially spherical particles having a smooth outer surface and essentially void-free interior are produced, consisting essentially of solid, cold-water insoluble vehicle comprising a physiologically acceptable, parenterally metabolizable protein or polysaccharide having dispersed therein a water-insoluble carrier loaded with radioisotopes, which are substantially non-leachable upon short term exposure to cold water. Such particles can be administered parenterally for diagnostic purposes, or for treatment with radioactive materials. On administration in this way, they are broken down or solubilized by the body fluids over a predeterminable period ranging from minutes to several days, whereupon the radioisotopic material is excreted from the body thus limiting exposure to the radiation.

BACKGROUND OF THE INVENTION (1) Field of the invention

It has heretofore been known to encapsulate natural products for food orpharmaceutical use in proteinaceous materials, such as gelatin andalbumin, and even small spherical particles of such encapsulatedmaterials have been made, e.g. by processes such as those disclosed inU.S. Pats. 3,137,631; 3,016,308; 3,202,731; 2,800,457 and the like.These prior art processes, however, either produce capsular materialswherein a central core is surrounded by a thin shell, e.g. albumin orgelatin; or, for purposes of obtaining materials that can be handled, orstored under adverse conditions, result in severe denaturization of theprotein so that its solubility and other properties are impaired. Suchmaterials are not suitable for parenteral administration in the animalorganism. Similarly, while the use of radioisotope-labeled particulatesparenterally in the animal body is known for diagnostic and treatmentpurposes, the materials heretofore used for such purposes have beenrelatively insoluble, very finely divided irregular or sphericalparticles which, when used, lodge in the body and remain there duringsubstantially the entire life of the radioisotope. Such particles, forexample, are shown in U.S. Pats. 3,334,050 and 3,147,225. While theseare very useful for certain purposes where long-continued radioisotopictreatment, for example, is desirable and advantageous, there are otherareas in which their use is less desirable and in some instances may becontra-indicated. Irregular macroaggregates of human serum albumin,labelled with radionuclides, have been used for diagnostic purposes.These materials cannot be prepared in narrow ranges of particle size andare prepared in particulate form directly in the solution in which theyare to be used; they cannot be dried and sized or otherwise treated, andthen resuspended.

SUMMARY OF THE INVENTION

The present invention provides means to prepare certain physiologicallyacceptable, parenterally metabolizable materials in spherical form, inhighly pure, undenatured condition so that these can be administeredparenterally as a solid without injury to the organism, and containingdispersed therein in a carrier radioisotopes which are useful fordiagnostic, prophylactic and treatment purposes. The invention alsocontemplates the provision of a process for making such particles andtheir concomitant or subsequent treatment to incorporate radioisotopestherein, and to modify their solubility characteristics without bringingabout denaturization which would prevent their absorption in the body.

Hereinafter, the material of which the particle, or matrix, in which theradioactive material is dispersed, is termed the "vehicle"; and thesubstance upon which the radioactivity is absorbed is called the"carrier."

The particulate compositions of the invention comprise a physiologicallyacceptable, solid, substantially water-insoluble (at body temperature)vehicle which can be metabolized, or degraded in a manner which does notform toxic residues, apparently by the enzymes or other metabolicmechanisms in the parenteral body fluids, such as blood, serum, plasma,lymph and the like. When so metabolized or degraded, these substancesare solubilized.

Dispersed in this vehicle is a relatively water-insoluble carrier forradioisotopic ions, and this carrier is required to be physiologicallyacceptable so as to be free from injurious toxic effects when releasedin the body by the metabolic mechanisms which solubilize the vehicle.The carrier further binds or contains the radioisotopes, as by ionexchange, or by incorporating the radioisotope ion as part of thecarrier, e.g. as the anion or cation of a salt.

Suitable vehicles for the particulate compositions of the invention arephysiologically acceptable proteinaceous substances such as albumin,gelatin, hemoglobin and the like; and polysaccharides, such as starch,glycogen, dextran, etc.

The carrier can be loaded with radioisotopes by insoluble saltformation, e.g. by forming silver iodide by reaction of silver nitratewith hydriodic acid, a portion of which is HI¹³¹ ; or by reacting bariumchloride with a solution of sulfuric acid containing a certain amount ofS³⁵ as sulfate ion. Another method of introducing a radioisotope into acarrier is by ion exchange or absorption, e.g. by absorbing Ce¹⁴⁴ onferric or aluminum hydroxide.

Suitable carriers include, for example, hydroxides of iron, chromium,aluminum and manganese; sulfates of barium, strontium and calcium, andsulfides of zinc, copper, tin, nickel and cobalt. Other metal saltswhich function usefully as carriers include chromates, e.g. of barium;halides, e.g. of silver; and carbonates, e.g. of calcium. These carriershave solubility product of the order of 1×10⁻ ⁴ or less. The carrier isemployed in amount at least sufficient to bind the radioisotope in thequantity used, but preferably is in excess thereof. Thus, up to about50% of carrier can be used, based on the weight of the vehicle.Preferably about 1 to 10% of carrier is incorporated in the vehicle.

For use in diagnostic procedures or treatment requiring radioisotopes tobe directed to a particular locale within the body, the vehicle isprepared in finely divided state, the sizes of the particles beingclosely controlled by sorting techniques so as to be in a narrow sizerange adapted to the specific use. Particles thus segregated into narrowranges can be from about 1/2 to 1000 microns in average diameter andpreferably the size ranges chosen do not vary more than about plus orminus 20% from the mean.

Preferably, spheroidal or essentially spherular particles are employedas being more uniform and more easily controlled with respect toradioisotope content and time of elimination from the body. Spherulesfrom 1/2 to 60 microns in diameter are most useful for diagnosticpurposes. Larger spherules, even up to 1 millimeter in diameter, can beused for certain therapeutic purposes. Being uniform in theirdimensions, spheroidal or spherular particles are more easily controlledwith respect to radioisotope content and time of elimination from thebody. Particularly, they are preferred because, by matching the diameterof the spherules to the size of body passages, e.g. arteries,capillaries, etc., one can predict their route through a healthy bodyand determine where they should lodge with high accuracy.

To make the particles of the invention, a convenient method consists informing a sol by dispersing the vehicle, e.g. a suitable protein orpolysaccharide, in warm water, adding an amount of finely dividedcarrier with bound radioisotope (which can readily be an amountcalculated to provide a desired level of radioactivity for each gram ofthe product after drying), and mixing until homogeneous, then causingthe vehicle to gel as by cooling or removing water, followed by drying.The dried material can be comminuted by grinding or the like to formparticles of the size desired, grading by sieves or the like beingentirely feasible.

Preferably, however, the aqueous vehicle containing the carrier andbound radioisotope is formed directly into tiny spheroids or spherulesby causing gelation to take place in that form. While these gelledparticles are prevented from coalescing, the water is removed and theparticles are dried to a free-flowing, unagglomerated form.

When thus prepared, the essentially cold water-insoluble particles canbe washed to remove surface contamination by radioisotopes. They can besubjected to heat treatment to modify their solubility, and screened orotherwise graded to desired size range. They can be soaked in water at37° C. for at least 15 minutes without leaching out any radioactivity.In many cases they can be thus treated for periods of hours or even dayswithout disintegration or loss of radioactivity. In physiological fluidssuch as blood serum, however, they soon begin to be broken down andeventually are completely solubilized.

Thus, for example, it has been found that by dispersing a solution ofalbumin, e.g. by stirring into warm, inert fluid which is immisciblewith the solution of albumin and in which the albumin itself is notsoluble, small spherules of the albumin are formed. The speed ofstirring, use of baffles and the like controls the size of the particlesobtained; empirical methods are used to establish parameters ofdispersion to yield spheroidal particles of any particle size.Alternatively and preferably for continuous production, tiny droplets ofthe aqueous liquid are injected through a small orifice into a movingstream of the warm, inert fluid. The water is removed from the albuminsolution through the medium of the warmed, inert fluid, which may bee.g. vegetable oil or hydrocarbon solvents, so that dry, practicallyperfectly round, free-flowing tiny spherules of albumin are obtained.These spherules are from 1 to 500 microns or even up to a millimeter indiameter and can be obtained through the process in very narrow,pre-determined size distribution ranges. They are substantiallyundenatured, and can be administered parenterally in the animalorganism. When so administered, it is surprisingly found that they arereadily broken down, probably by the enzymes in the body fluids, andconverted to soluble form.

The microspherules, e.g. of albumin, are made to contain radioisotopesby incorporating the selected carrier with radioisotopic material intothe solution of albumin before it is dispersed in the inert fluid.Alternatively, the vehicle is prepared containing unlabelled carrier.These are treated with a radionuclide solution. The spherules, whilefree from visible voids or bubbles, apparently are porous enough topermit the radionuclide to penetrate into the interior of the particlewhere it is absorbed upon the carrier. This procedure is especiallyuseful with radionuclides with very short half-life; e.g. indium 113m,as the absorption process requires a very short time and the particlescan be prepared in advance and treated with radionuclide immediatelybefore use. The radioisotopes cannot be leached from the resultingradioactive spherules upon immersion in water for periods of time offrom about 15 minutes up to several days.

The albumin referred to herein is broadly any of the several naturalproteins which are so described. Such albumins include those of egg,blood serum, milk and the like, as obtained from various animal species.For the purposes of this invention, the preferred albumins are animalalbumins from serum, human serum albumin, and in general, for eventualuse in a given animal organism, albumin obtained from the serum of thatorganism. Polysaccharides work equally well in this process.

Spherules formed from sol-forming proteins do not shrink greatly duringdrying; however, spherules formed from polysaccharides may shrink up to30% in diameter as they dry. Suitable allowance for such shrinkage musttherefore be made when particles of a particular size are sought.

Suitable inert liquids for the process of making the spherules of theinvention include vegetable oils, for example, corn oil, olive oil andthe like; low melting animal fats; mineral oils, particularly thosehaving boiling points above about 150° C.; inert halogenatedhydrocarbons, and the like. The function of the inert liquid is toremove water from the protein and to cause gelling, and it will beapparent that various solvents can be used to accomplish this end.

The radioisotopes which can be incorporated into the spherical particlesof albumin include such materials as cerium-144, iodine-131, yttrium-90,indium-114, indium-113, ytterbium-169, technetium-99, and any otherradionuclide which is capable of existing in ionic form and of forming asalt or other solid derivative. These are of course selected withrespect to the type and intensity of emitted radiation, to be adapted tothe use for which the particles are intended.

For use in diagnostic procedures, a suspension of the particles of theinvention, such as microspherules of albumin containing a radionuclide,are suspended in a pharmaceutical extending medium suitable forparenteral administration. This may be, e.g., physiological saline, ordextran or gelatin solutions. A quantity of such a compositioncontaining the desired amount of radioactivity, e.g. one millicurie, isinjected e.g. intravenously into the animal body. The material thusinjected circulates throughout the body in the blood stream and, becauseof the selected particle size, will lodge in a particular, predeterminedorgan, e.g. the lung. Radiation detectors, or autoradiography, may thenbe employed to visualize the organ. Because the microspherical particlesremain substantially intact for a short time in the animal organism, aperiod of time ranging up to several days is available for suchdiagnostic procedure. Thereafter, the body enzymes begin to attack thevehicle, causing it to become solubilized and absorbed. Theradioisotopic material, or its decay product, is, however, swept awayfrom the localized area in the blood stream and excreted, generally bythe kidneys.

For therapeutic or prophylactic use, the products are administered asdescribed above except that the activity is usually much higher, (e.g.50 millicuries) and the biodegradability of the particles is adjusted soas to retain the radionuclide until it has delivered the energy requiredfor these purposes.

It will be apparent that the particular vehicle or carrier chosen toprepare the particles of the invention which convey radioisotopes intopredetermined, temporary location in the body is not critical. It isonly necessary that the vehicle be physiologically acceptable, capableof being prepared in essentially insoluble form with respect to water at37° C. for at least a short period, and capable of being metabolized ordegraded by body fluids to soluble form. Likewise, the carrier is notcritical so long as it is likewise essentially insoluble in water andbinds the radioisotope so as to prevent radioactivity from being leachedout of the particles when soaked in water at 37° C. for a period of atleast 15 minutes.

The following specific examples will more clearly illustrate thespecific embodiments of the invention. In these examples, all parts areby weight unless otherwise specified. As a practical matter, radioactivematerials are in terms of their radiation level rather than by exactweight and wherever radiation level is mentioned, this is the exactamount of radionuclide used.

EXAMPLE 1

A solution was prepared containing 80 milligrams of ferric chloride andabout 1 milligram of cerium¹⁴⁴ chloride (activity 5 millicuries) in .2ml. of water. While stirring 10 percent aqueous sodium hydroxidesolution was slowly added until the pH of the mixture was about pH7-7.5. A gelatinous precipitate of ferric hydroxide containing about 5millicuries of radiocerium was formed. This was washed by centrifugationand decantation with distilled water.

The precipitate thus prepared was added to 4 ml. of a 25 percentsolution of human serum albumin in water. The mixture was carefullystirred until homogeneous, avoiding the formation of bubbles. Theresulting mixture was then injected through a hypodermic needle intoabout 1 liter of vegetable oil (cottonseed oil) which was heated toabout 30-50° C. The rate of stirring determines the ultimate size of thespherular material obtained. Using a container which is greater inheight than in diameter, with a 25 gauge hypodermic needle and stirringat about 500 r.p.m. with a 21/2 inches propeller-type stirrer,microspherular particles of about 10 to 20 microns in diameter areobtained. Stirring is continued while heating to 110° C. until all ofthe water in the microspheres is removed, as may be determined byremoval from the mixture of a small number of spheres to determinewhether or not they are still tacky. After removal of the water, theparticles are filtered away from the oil and washed with diethyl ether.Microspherular particles of human serum albumin as a vehicle, withradiocerium contained therein carried upon ferric hydroxide, areobtained. The microspheres are about 10 to 20 microns in diameter andare unagglomerated, free-flowing brown color.

The spherules thus obtained are washable in water at 37° C. Whensuspended in physiological saline solution, the spherules arebiodegraded and are 50% solubilized in less than a day after injectioninto test animals.

Somewhat higher temperatures can be employed in the process, accompaniedby an increase in the time required for biodegradation. Thus, forexample, the oil is heated to 135° C. and maintained there for 40minutes while stirring. Again, free-flowing, unagglomerated particles ofhuman serum albumin containing radiocerium in ferric hydroxide carrierare recovered. These are biodegraded and solubilized to the extent of50% in about one day.

Lower temperatures can be used for drying by heating at subatmosphericpressures conveniently by using a water aspirator or with a vacuum pump,reducing the temperature in proportion to the reduction of pressure.Particles thus produced are biodegraded and solubilized to the extent of50% in less than a day.

Particles heated at 160° C. are 50% solubilized in the animal body inabout 31/2 days; at 170° C., in about 33/4 days; and at 190° C., in overthirty days.

Similarly, when egg albumin is employed instead of human serum albumin,spherular particles are obtained which closely resemble the particlesfrom human serum albumin.

A homogeneous mixture is made containing 0.1 g. of finely dividedradiobarium sulfate (S³⁵, 0.5 millicurie) in 4 ml. of 25% aqueous humanserum albumin, and converted into spherules as described above, dryingat 110-130° C. Free-flowing, cream-colored radioactive spherules about10-20 microns in diameter are thus prepared.

In the same way, one millicurie of finely divided radio technetiumsulfide (Tc^(99m)) is dispersed in 4 ml. of 25% aqueous human serumalbumin and formed into 10-20 micron spherules. The radioactivity of theparticles has a short half-life.

EXAMPLE 2

Tiny spherical particles of albumin similar to those obtained in Example1 are also prepared as follows:

A solution containing 100 milligrams of ordinary, non-radioactive sodiumiodide in 8 ml. of water is mixed with 5 ml. of water containing 5millicuries of sodium iodide¹³¹. To this solution is added 10 percentaqueous silver nitrate, with stirring, until an excess of silver nitrateis present and no more silver iodide precipitates. The precipitate iscentrifuged down, the supernatant liquid decanted, and washed withdistilled water by repeatedly suspending the precipitate in water andcentrifuging, decanting the supernatant liquid, until the washings arefree from soluble silver iodide. The precipitate is carefully mixed into4 ml. of a 25 percent aqueous human serum albumin solution, avoiding theincorporation of air bubbles, until the mixture is homogeneous. Theresulting albumin-silver iodide mixture is injected into warm corn oilto form spherules, which are dried, as described in Example 1. Brown,free-flowing, unagglomerated spherules about 10 to 20 microns indiameter, containing silver nitrate in which an amount of radioactiveiodine¹³¹ is carried are thus obtained.

Alternatively, 300 microliters of water containing 2 millicuries ofradioiodine¹³¹ as radioactive sodium iodide is mixed with 100microliters of a 3 molar solution inactive sodium iodide as a carrier.This solution is mixed with 4 ml. of 25% aqueous human serum albumin.Vigorous stirring is used, avoiding bubble formation. Continuing thestirring, 125 microliters of 3 molar aqueous silver nitrate solution isslowly added. The solution becomes primrose yellow in color as colloidalsilver iodide is formed.

The colloidal suspension of silver iodide in albumin thus formed is madeinto microspherules as described in Example 1.

EXAMPLE 3

Radionuclide-free microspheres of albumin with ferric hydroxide are madeas described in Example 1, drying at 110-130° C., but leaving out theradiocerium chloride. These dry, free-flowing 10-20 micron spherules arereadily loaded with radionuclides as follows:

About one gram of the microspheres is added to a solution 5 millicuriesof radiocerium chloride in 10 ml. of water. The mixture is agitatedgently for 10 minutes at 37° C. After filtration or centrifugation andwashing over 60% of the radioactivity originally present in the liquidis found to be firmly fixed or absorbed in the spherules. Alternatively,ferric hydroxide is prepared as a swollen gelatinous precipitate fromferric chloride solution by carefully neutralizing it with dilute sodiumhydroxide solution. This precipitate is washed by centrifugation anddecantation with aliquots of water to remove excess alkali. Four ml. of25% aqueous human albumin is added to 0.1 gm. of the ferric hydroxide(dry basis) and the system is carefully mixed until it is homogeneous.This mixture is then formed into spherules as described in Example 1.

After drying at 110-130° C., the spherules are placed in a solution ofradioindium chloride with gentle agitation. Contact is maintained untilthe desired amount of radioactivity has been taken up by the beads. Forexample, in a solution originally containing 233,550 counts per minuteof In¹¹⁴, 60% is taken up in 5 minutes, 79.5% in 2 hours.

An aqueous solution of sodium iodide is prepared containing 12.7 mg./ml.of iodide ion. To 1 ml. of this is added an excess of 10% aqueous silvernitrate solution. The precipitated silver iodide is washed to removeexcess silver, and is mixed thoroughly with 0.5 ml. of a 25% aqueoussolution of human albumin. The mixture is formed into spherules anddried at 110-130° C. as described in Example 1.

After drying, the spherules are placed in a solution of radioactivesodium iodide (I¹³¹) and gently agitated. Contact is maintained untilthe desired amount of radioactivity has been taken up by the spherules.For example, in a solution originally containing 330,420 c.p.m., 99% istaken up in 10 minutes.

Alternatively, a solution of 25% aqueous human serum albumin containing10% sodium chloride is converted into spherules as described in Example1, drying at 110-130° C. One hundred milligrams of these are suspendedin 20 ml. of acetone and 1 ml. of 3 molar aqueous silver nitrate isadded. The suspension is stirred for half an hour at ambient or mildlyelevated temperature. Then it is filtered and washed thoroughly withwater and acetone. The spherules are again suspended in 10 ml. ofacetone and 25 microliters of a solution containing 0.5 millicurie ofratioactive sodium iodide (I¹²⁵) are added. After contacting thespherules with the radioactive solution for 17 hours, 99.75% of theradioiodide has been absorbed as shown by radio-assay. The thus labelledspherules are filtered off, washed with water and acetone and dried inair.

Similarly, a solution of 25% albumin containing 0.6% silver nitrate (dryweight basis) is converted into spherular particles in the mannerdescribed in Example 1. One hundred milligrams of these are suspended in10 ml. of water at 18° C.; 25 milliliters of an aqueous solutioncontaining 0.25 millicurie of radioactive sodium iodide (I¹²⁵) are addedand the suspension is agitated for one hour. Radio-assay then shows that67% of the radioiodine has been absorbed. The spherules are filteredoff, washed with water and acetone, and dried in air.

EXAMPLE 4

A solution is made by dissolving 1 gram of glycogen in 40 ml. of water,mixing and stirring while avoiding incorporation of bubbles. To this isadded about 80 milligrams of ferric hydroxide containing 1 milligram (orabout 5 millicuries) of radiocerium, as set forth in Example 1. Themixture is dispersed in a stirred bath of cottonseed oil which is keptat 65° C. until all of the glycogen dispersion has been introduced inthe form of small particles. Thereafter stirring is continued and thetemperature is raised to 105-110° C. and maintained there until all ofthe water has been removed from the particles.

The resulting particles, which are free-flowing, unagglomerated, tinyspherules about 10 to 20 microns in diameter, dissolve rapidly in water.To treat these particles to make them less soluble, they are heated at200° C. in the dry form for 30 minutes. Particles thus treated dissolvein physiological saline solution in approximately 20 minutes. If heatingin this manner is continued for two hours, the particles dissolve inphysiological saline solution in about 30 minutes. However, noradioactivity is leached from the particles if they are placed in waterat 37° C. for 15 minutes. If heated at 200° C. for 13 hours, theparticles do not dissolve in physiological saline solution. Theparticles are more rapidly solubilized in the body fluids than inphysiological saline solutions.

Substantially similar results are obtained if a solution of 1 gram ofstarch phosphate in 10 ml. of water is employed, to which radioceriumcarried upon ferric hydroxide is added. The mixture is dispersed intohot oil as set forth herein, and dried, to form tiny, free-flowing, dryspherical particles of starch labelled with radiocerium.

EXAMPLE 5

A solution of one gram of gelatin in 10 ml. of water was mixed withprecipitate of indium¹⁴⁴ /ferric hydroxide made according to Example 1.The mixing was continued until the system was homogeneous, convenientlyat ca. 60° C. When mixing was complete, the mixture was injected into aliter of rapidly stirred cottonseed oil, also at ca. 60° C. to dispersethe gelatin into tiny spherules. The temperature was raised to 110° C.and maintained there until the water was all evaporated. Afterfiltration and washing with ether, spherules of gelatin labelled withradioindium were obtained, about 20-30 microns in diameter asfree-flowing, unagglomerated particles.

EXAMPLE 6

A convenient method for continuous production of spheroidal particles isthe following: Four parts of a 25% aqueous solution of sodium chlorideis thoroughly mixed with 40 parts of a 25% aqueous solution of albumin.The mixture, at room temperature, is passed through a No. 27 needle intoa stream of cottonseed oil warmed to about 50° C., moving at the rate ofabout 12 feet per minute. The albumin-containing mixture breaks up intodroplets, which are suspended in the oil. The stream of droplets-in-oilis carried through a 50 ft. long tube, heated to ca. 115° C. This driesthe droplets to microspherules of about 20-50 microns diameter. The oiland dried spherules are run into a tube and after cooling, they arecollected, the oil being removed by filtration. After warming again toabout 50° C., the oil is recirculated.

Radioactive materials are incorporated into the spherules, when requiredfor use, by the process of post-loading described in Example 3.

What is claimed is:
 1. Tiny free-flowing, unagglomerated radioactiveparticles of the order of about one-half micron to 1 millimeter inlargest dimension, consisting essentially of a gelled vehicle ofphysiologically acceptable parenterally metabolizable sol-formingpolysaccharide of the class consisting of glycogen, starch and dextranor protein of the class consisting of albumin, gelatin and hemoglobinhaving dispersed therein a physiologically acceptable inorganic carrierfor radionuclides, said carrier having solubility product less thanabout 1×10⁻ ⁴, said carrier containing a radionuclide and being presentin said particles in amount ranging from that which is at least adequateto contain said radionuclide up to about 50% by weight based upon theweight of the vehicle, and said particle being resistant to leaching ofsaid radionuclide when immersed in water at 37° C. for at least about 15minutes.
 2. Particles according to claim 1 which are substantiallyspherular in form.
 3. Particles according to claim 1, in which thevehicle is a protein.
 4. Particles according to claim 1, in which thevehicle is a polysaccharide.
 5. Particles according to claim 1, in whichthe carrier is a metal salt.
 6. Spherules according to claim 2, whereinthe vehicle is albumin and the carrier is a metal salt.
 7. Spherulesaccording to claim 2, in which the vehicle is a polysaccharide and thecarrier is a metal salt.
 8. Spherules according to claim 2, in which thevehicle is albumin and the carrier is ferric hydroxide.
 9. Spherulesaccording to claim 2, in which the vehicle is albumin, the carrier issodium iodide and the radionuclide is I¹³¹.
 10. Spherules according toclaim 2, in which the vehicle is albumin, the carrier is ferrichydroxide and the radionuclide is cerium¹⁴⁴.
 11. Spherules according toclaim 2, in which the vehicle is albumin, the carrier is technetiumsulfide and the radionuclide is technetium 99^(m).
 12. Spherulesaccording to claim 2, in which the vehicle is glycogen and the carrieris ferric hydroxide.
 13. Spherules according to claim 2, in which thevehicle is glycogen, the carrier is ferric hydroxide and theradionuclide is cerium¹⁴⁴. .Iadd.
 14. Tiny, free-flowing, unagglomeratedparticles of the order of about one-half micron to one millimeter inlargest dimension adapted for containing radionuclides, consistingessentially of a gelled vehicle of physiologically acceptableparenterally metabolizable sol-forming polysaccharide of the classconsisting of glycogen, starch and dextran or protein of the classconsisting of albumin, gelatin and hemoglobin having dispersed therein aphysiologically acceptable inorganic carrier for radionuclides, saidcarrier having solubility product less than about 1×10⁻ ⁴, said carrierbeing present in said particles in amount ranging from that which is atleast sufficient to bind radionuclides in the quantity used up to about50% by weight based upon the weight of the vehicle, and said particleswhen administered parenterally in the animal organism, being broken downand converted to soluble form. .Iaddend..Iadd.
 15. Particles accordingto claim 14, which are substantially spherical in form. .Iaddend..Iadd.16. Particles according to claim 15, in narrow size range from aboutone-half to 60 microns in diameter.